Chronic urethral obstruction results in numerous alterations in the urinary bladder that impair both its storage and emptying properties. The detailed molecular descriptions of these changes and the associated effects on bladder voiding properties have not been clearly identified. We have previously shown that bladders subjected to outlet obstruction undergo specific alterations in expression of contractile, regulatory and structural proteins, leading to a shift in contractile properties from phasic to tonic. This research project is based upon the hypothesis that depressed voiding function during partial bladder outlet obstruction (PBOO) is caused by this remodeling which in the early phases results in a detrusor capable of generating enhanced bladder pressure but unable to adequately sustain pressure to complete emptying; continued remodeling leads to progressive contractile failure. To test this hypothesis, the following specific aims will be addressed using strips of detrusor muscle obtained from bladders from three groups of rabbits: sham, subjected to PBOO, and subjected to PBOO but reversed before study. Aim 1: To determine whether compromised voiding is caused by alterations in the contractile apparatus and/or passive properties of the detrusor. Aim 2: To determine whether a failure to sustain activation levels in the hypertrophied detrusor is the cause of the higher bladder post-void residual urine volume associated with PBOO. Aim 3: To determine whether the observed shift of the detrusor to more tonic smooth muscle characteristics during PBOO is reversed two weeks after removal of the obstruction. Aim 4: To determine which steps in the cellular signal transduction path-way(s) are altered by PBOO and if the alteration is reversed after removal of the obstruction. Aim 5: To determine if the "switch" from a phasic to a tonic-like contraction in response to PBOO is mediated by a change in caldesmon regulation or content. Aim 6: To determine if the change (loss/reoccurrence) in protein kinase C (PKC) dependent contractions is the "switch" that causes a mildly dysfunctional bladder to become irreversibly and severely dysfunctional. The results of these studies will identify the specific steps in excitation-contraction coupling of detrusor smooth muscle that are altered and thus may account for bladder dysfunction during outlet obstruction. Moreover, the results of these studies will also determine which alterations in contractile or regulatory proteins are associated with bladder remodeling.